Veno-arterial ECMO ventricular assistance as a direct bridge to heart transplant: A single center experience in a low-middle income country.

INTRODUCTION: The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a direct bridge to heart transplantation (BTT) is not common in adults worldwide. BTT with ECMO is associated with increased early/mid-term mortality compared with other interventions. In low- and middle-income countries (LMIC), where no other type of short-term mechanical circulatory support is available, its use is widespread and increasingly used as rescue therapy in patients with cardiogenic shock (CS) as a direct bridge to heart transplantation (HT). OBJECTIVE: To assess the outcomes of adult patients using VA-ECMO as a direct BTT in an LMIC and compare them with international registries. METHODS: We conducted a single-center study analyzing consecutive adult patients requiring VA-ECMO as BTT due to refractory CS or cardiac arrest (CA) in a cardiovascular center in Argentina between January 2014 and December 2022. Survival and adverse clinical events after VA-ECMO implantation were evaluated. RESULTS: Of 86 VA-ECMO, 22 (25.5%) were implanted as initial BTT strategy, and 52.1% of them underwent HT. Mean age was 46 years (SD 12); 59% were male. ECMO was indicated in 81% for CS, and the most common underlying condition was coronary artery disease (31.8%). Overall, in-hospital mortality for VA-ECMO as BTT was 50%. Survival to discharge was 83% in those who underwent HT and 10% in those who did not, p < .001. In those who did not undergo HT, the main cause of death was hemorrhagic complications (44%), followed by thrombotic complications (33%). The median duration of VA-ECMO was 6 days (IQR 3-16). There were no differences in the number of days on ECMO between those who received a transplant and those who did not. In the Spanish registry, in-hospital survival after HT was 66.7%; the United Network of Organ Sharing registry estimated post-transplant survival at 73.1% ± 4.4%, and in the French national registry 1-year posttransplant survival was 70% in the VA-ECMO group. CONCLUSIONS: In adult patients with cardiogenic shock, VA-ECMO as a direct BTT allowed successful HT in half of the patients. HT provided a survival benefit in listed patients on VA-ECMO. We present a single center experience with results comparable to those of international registries.

Comprehensive Phenotyping in Inflammatory Bowel Disease: Search for Biomarker Algorithms in the Transkingdom Interactions Context.

Inflammatory bowel disease (IBD) is the most common form of intestinal inflammation associated with a dysregulated immune system response to the commensal microbiota in a genetically susceptible host. IBD includes ulcerative colitis (UC) and Crohn's disease (CD), both of which are remarkably heterogeneous in their clinical presentation and response to treatment. This translates into a notable diagnostic challenge, especially in underdeveloped countries where IBD is on the rise and access to diagnosis or treatment is not always accessible for chronic diseases. The present work characterized, for the first time in our region, epigenetic biomarkers and gut microbial profiles associated with UC and CD patients in the Buenos Aires Metropolitan area and revealed differences between non-IBD controls and IBD patients. General metabolic functions associated with the gut microbiota, as well as core microorganisms within groups, were also analyzed. Additionally, the gut microbiota analysis was integrated with relevant clinical, biochemical and epigenetic markers considered in the follow-up of patients with IBD, with the aim of generating more powerful diagnostic tools to discriminate phenotypes. Overall, our study provides new insights into data analysis algorithms to promote comprehensive phenotyping tools using quantitative and qualitative analysis in a transkingdom interactions network context.

Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

PURPOSE: Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 17 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). METHODS: Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO), Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), DUOX2, Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. RESULTS: Four novel variants have been identified, two in TPO: c.2749-2 A > C and c.2752_2753delAG, [p.Ser918Cysfs*62] and two variants in DUOX2 gene: c.425 C > G [p.Pro142Arg] and c.2695delC [p.Gln899Serfs*21]. Eighteen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic biallelic variants in TPO and DUOX2 in 7 and 2 patients, respectively. We also detected a potentially pathogenic monoallelic variant in TPO and DUOX2 in 7 and 1 patients respectively. CONCLUSIONS: 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis.

KANSL2 is an integral subunit of the nonspecific lethal (NSL) chromatin-modifying complex that contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. Cancer Res; 76(18); 5383-94. ©2016 AACR.

Compound heterozygous DUOX2 gene mutations (c.2335-1G>C/c.3264_3267delCAGC) associated with congenital hypothyroidism. Characterization of complex cryptic splice sites by minigene analysis.

Iodide Organification defects (IOD) represent 10% of cases of congenital hypothyroidism (CH) being the main genes affected that of TPO (thyroid peroxidase) and DUOX2 (dual oxidasa 2). From a patient with clinical and biochemical criteria suggestive with CH associated with IOD, TPO and DUOX2 genes were analyzed by means of PCR-Single Strand Conformation Polymorphism analysis and sequencing. A novel heterozygous compound to the mutations c.2335-1G>C (paternal mutation, intron 17) and c.3264_3267delCAGC (maternal mutation, exon 24) was identified in the DUOX2 gene. Ex-vivo splicing assays and subsequent RT-PCR and sequencing analyses were performed on mRNA isolated from the HeLa cells transfected with wild-type and mutant pSPL3 expression vectors. The wild-type and c.2335-1G>C mutant alleles result in the complete inclusion or exclusion of exon 18, or in the activation of an exonic cryptic 5' ss with the consequent deletion of 169 bp at the end of this exon. However, we observed only a band of the expected size in normal thyroid tissue by RT-PCR. Additionally, the c.2335-1G>C mutation activates an unusual cryptic donor splice site in intron 17, located at position -14 of the authentic intron 17/exon 18 junction site, with an insertion of the last 14 nucleotides of the intron 17 in mutant transcripts with complete and partial inclusion of exon 18. The theoretical consequences of splice site mutation, predicted with the bioinformatics NNSplice, Fsplice, SPL, SPLM and MaxEntScan programs were investigated and evaluated in relation with the experimental evidence. These analyses confirm that c.2335-1G>C mutant allele would result in the abolition of the authentic splice acceptor site. The results suggest the coexistence in our patient of four putative truncated proteins of 786, 805, 806 and 1105 amino acids, with conservation of peroxidase-like domain and loss of gp91(phox)/NOX2-like domain. In conclusion a novel heterozygous compound was identified being responsible of IOD. Cryptic splicing sites have been characterized in DUOX2 gene for the first time. The use of molecular biology techniques is a valuable tool for understanding the molecular pathophysiology of this type of thyroid defects.

Kinetic characterization of human thyroperoxidase. Normal and pathological enzyme expression in Baculovirus system: a molecular model of functional expression.

BACKGROUND: Human thyroperoxidase (hTPO) is a membrane-bound glycoprotein located at the apical membrane of the thyroid follicular cells which catalyzes iodide oxidation and organification in the thyroglobulin (TG) tyrosine residues, leading to the thyroid hormone synthesis by coupling of iodotyrosine residues. Mutations in hTPO gene are the main cause of iodine organification defects (IOD) in infants. METHODS: We investigated the functional impact of hTPO gene missense mutations previously identified in our laboratory (p.C808R, p.G387R and p.P499L). In order to obtain the whole wild-type (WT) coding sequence of hTPO, sequential cloning strategy in pGEMT vector was carried out. Then, site-directed mutagenesis was performed. WT and mutant hTPOs were cloned into the pAcGP67B transfer vector and the recombinant proteins were expressed in Baculovirus System, purified and characterized by SDS-PAGE and Western blot. Moreover, we report for the first time the kinetic constants of hTPO, of both WT and mutant enzymes. RESULTS: The functional evaluation of the recombinant hTPOs showed decreased activity in the three mutants with respect to WT. Regarding to the affinity for the substrate, the mutants showed higher Km values with respect to the WT. Additionally, the three mutants showed lower reaction efficiencies (Vmax/Km) with respect to WT hTPO. CONCLUSIONS: We optimize the expression and purification of recombinant hTPOs using the Baculovirus System and we report for the first time the kinetic characterization of hTPOs.

Randomised clinical trial: mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease--a double-blind, randomised, placebo-controlled study.

BACKGROUND: Placebo-controlled studies in maintaining remission of symptomatic uncomplicated diverticular disease (SUDD) of the colon are lacking. AIM: To assess the effectiveness of mesalazine and/or probiotics in maintaining remission in SUDD. METHODS: A multicentre, double-blind, placebo-controlled study was conducted. Two hundred and ten patients were randomly enrolled in a double-blind fashion in four groups: Group M (active mesalazine 1.6 g/day plus Lactobacillus casei subsp. DG placebo), Group L (active Lactobacillus casei subsp. DG 24 billion/day plus mesalazine placebo), Group LM (active Lactobacillus casei subsp. DG 24 billion/day plus active mesalazine), Group P (Lactobacillus casei subsp. DG placebo plus mesalazine placebo). Patients received treatment for 10 days/month for 12 months. Recurrence of SUDD was defined as the reappearance of abdominal pain during follow-up, scored as ≥5 (0: best; 10: worst) for at least 24 consecutive hours. RESULTS: Recurrence of SUDD occurred in no (0%) patient in group LM, in 7 (13.7%) patients in group M, in 8 (14.5%) patients in group L and in 23 (46.0%) patients in group P (LM group vs. M group, P = 0.015; LM group vs. L group, P = 0.011; LM group vs. P group, P = 0.000; M group vs. P group, P = 0.000; L group vs. P group, P = 0.000). Acute diverticulitis occurred in six group P cases and in one group L case (P = 0.003). CONCLUSION: Both cyclic mesalazine and Lactobacillus casei subsp. DG treatments, particularly when given in combination, appear to be better than placebo for maintaining remission of symptomatic uncomplicated diverticular disease. (ClinicalTrials.gov: NCT01534754).

New insights into thyroglobulin gene: molecular analysis of seven novel mutations associated with goiter and hypothyroidism.

The thyroglobulin (TG) gene is organized in 48 exons, spanning over 270 kb on human chromosome 8q24. Up to now, 62 inactivating mutations in the TG gene have been identified in patients with congenital goiter and endemic or non-endemic simple goiter. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report 13 patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and imaging evaluation. Single-strand conformation polymorphism (SSCP) analysis, endonuclease restriction analysis, sequencing of DNA, genotyping, population screening, and bioinformatics studies were performed. Molecular analyses revealed seven novel inactivating TG mutations: c.378C>A [p.Y107X], c.2359C>T [p.R768X], c.2736delG [p.R893fsX946], c.3842G>A [p.C1262Y], c.5466delA [p.K1803fsX1833], c.6000C>G [p.C1981W] and c.6605C>G [p.P2183R] and three previously reported mutations: c.886C>T [p.R277X], c.6701C>A [p.A2215D] and c.7006C>T [p.R2317X]. Six patients from two families were homozygous for p.R277X mutation, four were compound heterozygous mutations (p.Y107X/p.C1262Y, p.R893fsX946/p.A2215D, p.K1803fsX1832/p.R2317X), one carried three identified mutations (p.R277X/p.C1981W-p.P2183R) together with a hypothetical micro deletion and the remaining two siblings from another family with typical phenotype had a single p.R768X mutated allele. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of altered TG folding as a consequency of truncated TG proteins and missense mutations located in ACHE-like domain or that replace cysteine.

Pili annulati coincident with alopecia areata, autoimmune thyroid disease, and primary IgA deficiency: case report and considerations on the literature.

Pili annulati is a rare autosomal dominant hair disorder clinically characterized by a pattern of alternating bright and dark bands of the hair, the bright bands appearing dark if observed by transmitted light. This pattern is due to the periodic occurrence of air-filled cavities along the hair cortex which scatter and reflect the light while precluding its transmission. A susceptibility region, including a possibly responsible Frizzled gene, has been mapped to the telomeric region of chromosome 12q, although a specific mutation has not been identified. The condition has sometimes been observed in concurrence with alopecia areata, and in this paper we report a case in whom the concomitant severe alopecia areata was associated with autoimmune thyroid disease and primary IgA deficiency - a quadruple complex which, to our knowledge, has never been previously described. The occurrence of multiple immune disorders in the same patient affected by pili annulati could represent a key to understanding the high prevalence of alopecia areata in this condition. Specifically, in individuals predisposed to autoimmune disease, the molecular alterations that cause the anatomical changes of pili annulati could prompt the immune response against the hair root that underlies alopecia areata.

Congenital goitrous hypothyroidism: mutation analysis in the thyroid peroxidase gene.

BACKGROUND: Iodide organification defect (IOD) is characterized by a reduced ability of the thyroid gland to retain iodide resulting in hypothyroidism. Mutations in thyroid peroxidase (TPO) gene appear to be the most common cause of IOD and are commonly inherited in an autosomal recessive fashion. The TPO gene is located on the chromosome 2p25. It comprises 17 exons, covers approximately 150 kb of genomic DNA and codes 933 amino acids. OBJECTIVES: In this study, we characterize the clinical and molecular basis of seven patients from four unrelated families with congenital hypothyroidism (CH) because of IOD. DESIGN AND METHODS: All patients underwent clinical, biochemical and imaging evaluation. The promoter and the complete coding regions of the human TPO along with the flanking intronic regions were analysed by single-strand conformation polymorphism analysis and direct DNA sequencing. Segregation analysis of mutations was carried out, and the effect of the novel missense identified mutations was investigated by 'in silico' studies. RESULTS: All subjects had congenital and persistent primary hypothyroidism. Three novel mutations: c.796C>T [p.Q266X], c.1784G>A [p.R595K] and c.2000G>A [p.G667D] and a previously reported mutation: c.1186_1187insGGCC [p.R396fsX472] have been identified. Four patients were compound heterozygous for p.R396fsX472/p.R595K mutations, two patients were homozygous for p.R595K, and the remaining patient was a compound heterozygous for p.Q266X/p.G667D. CONCLUSIONS: Our findings confirm the genetic heterogeneity of TPO defects and the importance of the implementation of molecular studies to determinate the aetiology of the CH with dyshormonogenesis.

Postsurgical paracicatricial cutaneous satellitosis of giant cell tumour of the tendon sheath, localized type.

Tenosynovial giant cell tumour (localized type) is a tumour of tendon sheaths and interphalangeal joints, affecting the digits and arising from the synovium. It is characterized by a proliferation of mononuclear cells and osteoclast-like polykaryocytes. Its propagation to the skin is an exceptional event, which can take place either in localized form in the fingertips (localized type) or in the rare diffuse form called giant cell tumour of the tendon sheath (diffuse type). We report here a case of giant cell tumour with cutaneous satellites, which appeared close to and around the surgical scar following the excision of the primary lesion, in a 9-year-old boy. In the cutaneous satellites, a few signs of transformation could be observed, consisting of the lack of stroma and pronounced cellularity characterized by sheets of rounded synovial-like cells admixed with multinucleated giant cells and xanthoma cells. No relapse was observed 1 year after a plastic surgery procedure (complete replacement of the involved skin). Diffuse lesions usually represent a diagnostic problem in comparison with their localized counterparts. The malignant transformation of an originally typical tenosynovial giant cell tumour is a rare but well-documented event. Our case seems to represent a typical example because the pronounced cellularity might wrongly lead to a diagnosis of malignancy.

Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene.

Thyroid Hormone Receptor beta (THRB) defects, typically transmitted as autosomal dominant traits, cause Resistance to Thyroid Hormone (RTH). We analyzed the THRB gene in thirteen South American patients with clinical evidence RTH from eleven unrelated families. Sequence analysis revealed seven novel missense mutations. Four novel mutations were identified in exon 9. The first, a c.991A>G transition which originates a substitution of asparagine by aspartic acid (p.N331D). The second nucleotide alteration consists of a guanine to cytosine transversion at position 1003 (c.1003G>C) and results in substitution of the alanine at codon 335 by proline (p.A335P). The third mutation, a c.1022T>C transition produces a change of leucine by proline (p.L341P). The fourth mutation detected in exon 9 was a c.1036C>T transition which replaces the leucine at codon 346 by phenylalanine (p.L346F). The sequencing of the exon 10 detected three novel missense mutations. The first, a c.1293A>G transition changing isoleucine 431 for methionine (p.I431M). The second, the cytosine at position 1339 was replaced by adenine (c.1339C>A) resulting in the replacement of proline by threonine (p.P447T). The third mutation detected in exon 10 was a c.1358C>T transition resulting in the substitution of proline at codon 453 by leucine (p.P453L). Finally, sequencing analysis of the THRB gene revealed three substitutions previously described (p.A268G, p.P453T and p.F459C). The p.P453T was found in two patients. In conclusion, we report thirteen patients with RTH caused by heterozygous mutations of the THRB gene. Seven of the identified mutations correspond to novel substitutions.

Sequential treatment with lamivudine and alpha-interferon in anti-HBe-positive chronic hepatitis B patients: a pilot study.

BACKGROUND: In chronic hepatitis B, long-term use of alpha interferon is hampered by side effects, and long-term treatment with nucleos(t)ide analogues is burdened by drug-resistant mutants. We hypothesized that alternate rounds of lamivudine and alpha interferon might circumvent previous shortcomings. AIM: To evaluate efficacy of sequential lamivudine or IFN-alpha2b monotherapies in preventing occurrence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants and achieving virological and biochemical response. METHODS: Fifteen patients with hepatitis B surface antigen, anti-HBe-positive chronic hepatitis received four consecutive rounds of monotherapy with lamivudine (100 mg/day), IFN-alpha2b (5MU/tiw), lamivudine, IFN-alpha2b. Serum HBV-DNA levels were evaluated during and off treatment, HBV polymerase and pre-core/core regions sequenced. RESULTS: End-of-treatment response was achieved in 10 patients (67%). One patient did not respond, a second developed genotypic resistance at week 24. A rebound in viremia occurred in three patients at week 48. Six patients (40%) remained sustained responders. Triple promoter mutations at nucleotides 1762-1764-1896 prevailed in non-responders (60%) as compared to responders (20%). L180M/M204V mutations were identified during virological breakthrough. CONCLUSION: Sequential approach of alternate rounds of lamivudine or interferon may help patients to tolerate a prolonged schedule of therapy and protect them from emergence of viral strains.

Treatment with botulinum toxin of octo-nonagerians with oesophageal achalasia: a two-year follow-up study.

BACKGROUND: Treatment of oesophageal achalasia with intrasphincteric injections of botulinum toxin has proved to be a successful alternative treatment modality. However, little is known about its long-term effects in very old patients. AIM: To evaluate the effects of such treatment in octo-nonagerians during a 2-year follow-up period. PATIENTS AND METHODS: Thirty-three patients with idiopathic oesophageal achalasia (range 81-94 years) entered the study. After basal evaluation and screening procedures, 100 U of botulinum toxin was injected at the lower oesophageal sphincter, and the procedure was repeated 1 month later. Data were collected at baseline and were compared after 1 and 2 years following the procedure. RESULTS: Seventy-eight per cent of patients were considered responders at 1 year and 54% were considered responders at 2 years. The weight gain at the end of the follow-up period was 2 (0-3) kg. No significant relationship was found between baseline lower oesophageal sphincter pressure and symptoms score after 1 and 2 years of follow-up; moreover, no major complications of botulinum toxin therapy were reported. CONCLUSION: Treatment of very old achalasic patients with botulinum toxin is safe, effective and yields good quality of life in a substantial proportion of these subjects.

Proton-pump inhibitors and outcome of endoscopic hemostasis in bleeding peptic ulcers: a series of meta-analyses.

OBJECTIVE: To perform meta-analyses of studies on outcome of bleeding ulcers of different proton-pump inhibitors (PPIs) regimens, after stratification of patients by endoscopic stigmata, and analysis of studies with and without endotherapy. METHODS: A total of 35 randomized trials comparing PPIs to placebo and/or H2-receptor antagonists (H2RAs) in 4,843 patients with high-risk endoscopic stigmata were retrieved. Outcomes were rebleeding, surgery, and mortality. RESULTS: Monotherapy with oral or bolus PPIs was superior to placebo and H2RAs in reducing rebleeding in both bleeders and nonbleeders at index endoscopy; the need for surgery was reduced only when compared to H2RAs. In nonbleeders, PPI monotherapy was as effective as a combination of endotherapy with H2RAs. A combination of endotherapy with PPIs was superior to monotherapy in reducing bleeding and surgery, and superior to endotherapy alone in minimizing rebleeding, but not surgery; the benefit was lost when confronted to endotherapy plus H2RAs, whether PPIs were given as infusion or bolus. By pooling data from studies comparing high doses of PPIs as continuous infusion versus regular doses as intermittent bolus, rebleeding, surgery, and mortality were not significantly different. CONCLUSIONS: Combination of endotherapy with either PPIs or H2RAs is indicated for nonbleeding ulcers at endoscopy with the intent to reduce rebleeding and surgery. Its value may extend to bleeding lesions, but current data are scanty. The benefit appears to be independent from route and doses of PPIs, as oral, bolus, or infusional methods are all effective.

Colonic motility in man: features in normal subjects and in patients with chronic idiopathic constipation.

The human colon is still a relatively unknown viscus, especially concerning its motor activity. However, in recent years, techniques have been perfected that allow a better understanding of colonic motility, especially through prolonged recording periods. In this way, it has been demonstrated that the viscus contracts according to a circadian trend, is responsive to physiological stimuli (meals, sleep), and features high amplitude, propulsive contractions that are part of the complex dynamic of the defecatory process. These physiological properties and their alterations in patients with chronic idiopathic constipation are reviewed in this article.

Use of polyethylene glycol solution in slow transit constipation.

Patients with long-standing functional slow-transit constipation were treated with low daily doses of polyethylene glycol solutions. Bowel frequency, stool consistency and colonic transit time improved markedly during the treatment. No relevant side-effects were reported during the study period.

Constipation: a common problem in patients with neurological abnormalities.

Constipation is a frequent complaint among patients with different neurological diseases. This review provides a brief account of the numerous conditions affecting the central, peripheral and intrinsic (enteric) nervous systems in which constipation can be the only clinical manifestation or a component of a complex syndrome. Recent neuropathophysiological acquisitions show that any structural or functional impairment of the intrinsic innervation of the gut, including both developmental (i.e., Hirschsprung's disease and intestinal neuronal dysplasia) and acquired (i.e., either degenerative or inflammatory neuropathies) disorders, can be associated with constipation. Constipation may also arise from derangements of the peripheral nervous system, including diabetes and primary chronic autonomic failure (pandysautonomias). Finally, in the central nervous system, a wide array of disorders (post-traumatic, degenerative, ischaemic or neoplastic) are recognized to determine bowel dysfunction, ultimately leading to constipation. Further understanding of the fine pathophysiological mechanisms through which the intrinsic and extrinsic nerve supplies to the digestive system are involved in idiopathic constipation or in diseases generating this symptom will hopefully lead to a better treatment of this frequent pathological condition.

Intact colonic motor response to sudden awakening from sleep in patients with chronic idiopathic (slow-transit) constipation.

PURPOSE: There are few data about the relationships between colonic motor behavior and higher brain functions, such as sleep. Previous studies were done in healthy subjects, and it is unknown whether patients with functional motor disorders of the colon behave differently. This study was designed to characterize colonic motor activity in patients with constipation, both during sleep and after sudden awakening, and to compare it with that of healthy subjects. Our working hypothesis was that patients with constipation would have an impaired response to sudden awakening. PATIENTS AND METHODS: Twelve chronically constipated women, 22 to 49 years old, were recruited for the study, and their data were compared with those obtained from 12 healthy female volunteers, 21 to 38 years old. Manometric studies were performed in the descending and sigmoid colon for 30 minutes during sleep (immediately before awakening) and 30 minutes after being awakened suddenly. A motility index was calculated before and after the stimulus. RESULTS: In both groups motility in the descending and the sigmoid colon was almost absent during sleep and significantly increased after sudden awakening. No difference in postawakening values was found between patients with constipation and controls. CONCLUSIONS: In patients with chronic constipation, the brain-gut control of some fundamental mechanisms governing colonic motility is preserved. These data suggest that the alterations of colonic motility described in chronic constipation may be caused by an intrinsic dysfunction of the viscus.

The nutcracker esophagus: a late diagnostic yield notwithstanding chest pain and dysphagia.

The nutcracker esophagus, a primary motor disorder, is frequently associated with noncardiac chest pain. However, there are no data on whether its diagnosis, as in other esophageal motility disorders, is delayed. Since the disorder is frequently heralded by alarming symptoms such as chest pain and dysphagia, diagnosis should be made as soon as possible. In this study we assessed the diagnostic delay, if any, in patients with the nutcracker esophagus. Moreover, we were interested in whether the abnormalities described in the distal esophagus could also involve the entire viscus. Fifty-four subjects (age range 23-78 yr) with the nutcracker esophagus were assessed for clinical and manometric variables as an overall group and after dividing them into subgroups according to their symptoms. The manometric variables were compared with those obtained in 61 controls (age range 21-67 yr). Overall, a diagnosis of nutcracker esophagus was made after an average period of 36 +/- 6 months, and surprisingly, this was not different in the various subgroups complaining of either chest pain, dysphagia, or both. Analysis of manometric variables showed that the mean amplitude of contractions was significantly higher in the patients' group at all esophageal body levels, even in the proximal portions. Again, there were no significant differences among the subgroups of nutcracker esophagus with respect to the symptoms. Notwithstanding the presence of alarming symptoms, such as chest pain and dysphagia, the nutcracker esophagus is diagnosed on average after 3 years from the onset of symptoms. Manometric assessment seems to confirm that this entity may indeed represent a primary esophageal motor disorder. The major dysfunction is due to an abnormal increase of contraction amplitude of the entire esophageal body.